With global air pollution massively on the rise, chronic obstructive pulmonary disease (COPD) with accompanying emphysema is a huge and growing health burden (HL-131). Worldwide, COPD affects 330 Mio people, is the third-leading cause of death with a rapidly rising toll in developing countries and an estimated cost of $2.1 trillion. COPD is a slowly progressive incurable disease of distal airways and lung parenchyma, eventually leading to respiratory failure and death. Chronic bronchitis with airway narrowing and alveolar wall destruction are pathologic hallmarks. Symptoms are mostly therapy-resistant. Airway epithelial cells and innate immune cells are key components of the pathogenesis of COPD, and emerging targets for urgently needed new therapies. Yet our understanding of how this specialized barrier epithelium is regulated is limited. Thus, it is paramount to identify new critical regulators of this tissue. Few airway mouse models of COPD exist and mostly focus on inflammatory regulators and proteases. The p73 gene, a relative of the p53 tumor suppressor with developmental roles in brain and germ cells, encodes two classes of isoforms called TAp73 (transcription factors with a transcriptional activation domain) and DeltaNp73 (DNp73, lacking the N-terminal TA domain and often a dominant-negative inhibitor of the p53/TAp63/TAp73). We discovered strong in vivo evidence for p73 in governing differentiation, integrity and renewal of airway (but not alveolar) epithelium. We find p73 expressed in human and mouse airway epithelium under differentiating conditions, in homeostasis and repair. Notably, p73-deficient mice exhibit severe airway defects and spontaneously develop progressive COPD followed by secondary emphysema. Thus, they are a powerful new genetic model for the epithelial airway component of the disease. Based on separable phenotypes in global (missing all p73 isoforms) and isoform-specific knockout (KO) mice, we identified three distinct functions of p73 isoforms within the airway epithelium. TAp73 appears to be a master regulator of motile multiciliogenesis in ciliated human and mouse cells, while DNp73 appears critical for airway epithelial cohesion and lifelong maintenance of basal stem/progenitor pools for regeneration and repair. Linking COPD to a gene of the p53 family are completely novel and exciting findings. They carry a high potential to greatly extend our understanding of normal airway biology and the pathophysiology of COPD. This proposal aims to firmly establish p73 as a major novel regulator, with the long-term goal of using this knowledge to develop innovative therapeutic strategies for chronic airway disease. Aim 1 will test the hypothesis that TAp73 is a master regulator of multiciliogenesis, using transcriptional and functional analyses in mouse and human primary organotypic cultures and in frog embryo skin. Aim 2 will test the hypothesis that DNp73 mediates cell-cell and cell-matrix cohesion within airway epithelium by exploiting a clever isoform- specific DNp73KO/reporter mouse. Aim 3 will use lineage tracing in mice and clonal tracheosphere assays to determine if DNp73 is an essential regulator of basal stem cells in homeostasis and repair.